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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Page viii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: 10.17226/25412.
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PREPUBLICATION COPY A Class Approach to Hazard Assessment of Organohalogen Flame Retardants Committee to Develop a Scoping Plan to Assess the Hazards of Organohalogen Flame Retardants Board on Environmental Studies and Toxicology Division on Earth and Life Studies A Consensus Study Report of

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This project was supported by Contract HHSP233201400020B between the National Academies of Sciences, Engineering, and Medicine and the Department of Health and Human Services. Any opinions, findings, con- clusions, or recommendations expressed in this publication are those of the authors and do not necessarily re- flect the view of the organizations or agencies that provided support for this project. Digital Object Identifier: https://doi.org/10.17226/25412 Additional copies of this publication are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2019 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested Citation: National Academies of Sciences, Engineering, and Medicine. 2019. A Class Approach to Hazard Assessment of Organohalogen Flame Retardants. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25412. Prepublication Copy

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Acad- emy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. C. D. Mote, Jr., is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medi- cine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public under- standing in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.national academies.org. Prepublication Copy

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. Prepublication Copy

COMMITTEE TO DEVELOP A SCOPING PLAN TO ASSESS THE HAZARDS OF ORGANOHALOGEN FLAME RETARDANTS Members DAVID C. DORMAN (Chair), North Carolina State University, Raleigh, NC HUGH A. BARTON (retired), Pfizer, Groton, CT KAREN BLACKBURN, Procter & Gamble Company, Cincinnati, OH JOHN BUCHER, National Institute of Environmental Health Sciences, Durham, NC JULIE L. DANIELS, University of North Carolina at Chapel Hill, Chapel Hill, NC JENNIFER L. FREEMAN, Purdue University, West Lafayette, IN KAMEL MANSOURI, Integrated Laboratory Systems, Raleigh, NC CARMEN MESSERLIAN, Harvard T.H. Chan School of Public Health, Boston, MA DAVID M. REIF, North Carolina State University, Raleigh, NC GINA M. SOLOMON, Public Health Institute, Oakland, CA CHIHAE YANG, Molecular Networks GMbH, Columbus, OH Staff ELLEN K. MANTUS, Project Director SUSAN N.J. MARTEL, Senior Program Officer RADIAH ROSE-CRAWFORD, Manager, Editorial Projects JESSICA WOLFMAN, Senior Program Assistant Sponsor U.S. CONSUMER PRODUCT SAFETY COMMISSION Prepublication Copy v

BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Members WILLIAM H. FARLAND (Chair), Colorado State University, Fort Collins, CO LESA AYLWARD, Summit Toxicology, LLP, Falls Church, VA ANN M. BARTUSKA, Resources for the Future, Washington, DC RICHARD A. BECKER, American Chemistry Council, Washington, DC E. WILLIAM COLGLAZIER, American Association for the Advancement of Science, Washington, DC DOMINIC M. DITORO, University of Delaware, Newark, DE DAVID C. DORMAN, North Carolina State University, Raleigh, NC GEORGE GRAY, George Washington University, Washington, DC R. JEFFREY LEWIS, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ GERMAINE M. BUCK LOUIS, George Mason University, Fairfax, VA ROBERT PERCIASEPE, Center for Climate and Energy Solutions, Arlington, VA REZA J. RASOULPOUR, Dow AgroSciences, Indianapolis, IN JOAN B. ROSE, Michigan State University, East Lansing, MI GINA M. SOLOMON, Public Health Institute, Oakland, CA DEBORAH L. SWACKHAMER, University of Minnesota, St. Paul, MN JOSHUA TEWKSBURY, Future Earth, Boulder, CO PETER S. THORNE, University of Iowa, Iowa City, IA Staff CLIFFORD DUKE, Director ELLEN K. MANTUS, Scholar and Director of Risk Assessment RAYMOND A. WASSEL, Scholar and Director of Environmental Studies SUSAN N.J. MARTEL, Senior Program Officer for Toxicology LAURA LLANOS, Financial Associate TAMARA DAWSON, Program Associate vi Prepublication Copy

Acknowledgments This Consensus Study Report was reviewed in draft form by persons chosen for their diverse per- spectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets institutional standards of quality, objec- tivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript re- main confidential to protect the integrity of the deliberative process. We thank the following for their review of this report: Vinicius Alves, University of North Carolina, Chapel Hill Joseph Braun, Brown University Weisueh Chiu, Texas A&M University Nigel Greene, AstraZeneca Richard Judson, US Environmental Protection Agency Andres Kortenkamp, Brunel University, London Eugene Muratov, University of North Carolina, Chapel Hill Reza Rasoulpour, Dow AgroSciences Heather Stapleton, Duke University David Volz, University of California, Riverside Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report, nor did they see the final draft before its release. The review of the report was overseen by David Allison, Indiana University, and Joseph Rodricks, Ramboll Environ, who were responsible for making certain that an independent exami- nation of the report was carried out in accordance with institutional procedures and that all review com- ments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies. The committee gratefully acknowledges the staff of the US Consumer Product Safety Commission for their presentations to the committee during open sessions. The committee is also grateful for the assis- tance of Norman Grossblatt who served as the report editor. Prepublication Copy vii

Contents SUMMARY ......................................................................................................................................................... 1 1 INTRODUCTION........................................................................................................................................ 5 Conceptual Advantages of a Class Approach, 5 Petition to Ban Organohalogen Flame Retardants in Selected Consumer Products, 6 Statement of Task, 7 Committee’s Approach to Its Task, 8 Organization of This Report, 8 References, 9 2 HAZARD ASSESSMENT SCOPING PLAN .......................................................................................... 10 Determine the Viability of a Class Approach, 10 Survey the Literature, 15 Search the Literature and Extract Data, 16 Evaluate and Integrate Data, 16 Integrating a Hazard Assessment That Uses a Class Approach into Risk Assessment, 20 Improved Efficiency and Cost-Effectiveness, 22 Conclusions, 22 References, 22 3 A CLASS APPROACH TO EVALUATING ORGANOHALOGEN FLAME RETARDANTS: CASE STUDIES ........................................................................................................... 25 Can Organohalogen Flame Retardants Be Defined as a Single Class?, 25 Definition of Subclasses of Organohalogen Flame Retardants, 27 Survey of the Literature, 27 Search of the Literature, 29 Case Study 1: Polyhalogenated Organophosphates, 32 Case Study 2: Polyhalogenated Bisphenol Aliphatics, 39 Addressing Discordant Data, 45 Projected Timeline and Costs, 47 Conclusions, 47 References, 47 APPENDIXES A BIOGRAPHIC INFORMATION ON THE COMMITTEE TO DEVELOP A SCOPING PLAN TO ASSESS THE HAZARDS OF ORGANOHALOGEN FLAME RETARDANTS ........... 56 B METHODOLOGIC DETAILS OF ANALYSES TO EVALUATE FEASIBILITY OF CLASS APPROACH AND TO DEFINE SUBCLASSES .................................................................... 59 C METHODOLOGIC DETAILS OF LITERATURE SURVEYS AND SEARCHES ......................... 71 D SUMMARY OF ZEBRAFISH STUDIES ............................................................................................. 84 Prepublication Copy ix

Contents BOXES, FIGURES, AND TABLES BOXES 1-1 Statement of Task, 7 1-2 Definitions of Terms Used in This Report, 8 2-1 OECD Guidance on Development of Categories under REACH, 12 2-2 An Example of a Potentially Hazardous Subclass, 18 2-3 A Tiered Approach for Assessing a Subclass on Which There Are No Relevant Toxicity Data, 19 3-1 An OFR Inventory, 26 3-2 Identification of Analogues to the OFR Seed Chemicals, 26 3-3 Use of NAM Data in Regulatory Decision-Making, 32 FIGURES S-1 Scoping plan to conduct a hazard assessment for the Consumer Product Safety Commission by using a class approach, 3 2-1 Scoping plan to conduct a hazard assessment for the Consumer Product Safety Commission by using a class approach, 11 2-2 An illustrative example for building confidence in the derivation of health reference values when using a read-across approach, 19 3-1 Substructures identified in OFR seed chemicals, 27 3-2 Histogram of data availability for the seed chemicals, 30 3-3 Histogram of data availability for the expanded set of chemicals, 31 3-4 Representative members of the polyhalogenated organophosphate subclass, 33 3-5 Representative members of polyhalogenated bisphenol aliphatics, 41 B-1 Standardization of structures to provide QSAR-ready structures amenable to modeling: desalted, stereochemistry-stripped, tautomers and nitro groups standardized, valence corrected, structures neutralized when possible, and duplicates removed, among other steps, 61 B-2 KNIME workflow used to identify organohalogens from DSSTox and determine analogues of OFR seed chemicals, 62 B-3 Principal components analysis of the seed OFRs (shown as red stars) and analogues (shown as green dots). Loadings are shown as blue projections, 64 B-4 Enrichment sites of OFRs from seed list and expanded set of analogues, 64 B-5 Principal component analysis that used the highest selected descriptors that resulted from the GA procedure: OFRs (shown as red stars) and analogues (shown as green dots), 65 B-6 Major chemotypes found in OFR seed set, 66 B-7 Screenshot of OFR categories and matching structures in ChemoTyper, 68 C-1 Explicit mapping of data availability for inventory chemicals, 72 C-2 Histogram of data availability for inventory chemicals, 73 C-3 Histogram of data availability for the expanded set of chemicals, 74 C-4 Heatmap that represents availability of Tox21data on the chemicals in the OFR inventory, 76 C-5 Heatmap that represents availability of ToxCast data on the chemicals in the OFR inventory, 77 TABLE 3-1 Chemotypes Identified in OFR Seed Chemicals That Have Been Associated with Predicted Biologic Activity, 28 3-2 OFR Subclasses Formulated by Using Chemotypes and Predicted Biologic Activity, 28 3-3 Members of the Polyhalogenated Organophosphate Subclass, 33 3-4 Genotoxicity Data on the Polyhalogenated Organophosphate Subclass, 34 3-5 Polyhalogenated Organophosphate Chronic Toxicity Studies, 34 3-6 Available Human Epidemiologic Data on Organophosphate Flame Retardants, 36 x Prepublication Copy

Contents 3-7 Developmental Toxicity of Polyhalogenated Organophosphates, 38 3-8 Zebrafish Teratology and Developmental Neurotoxicity Studies of Polyhalogenated Organophosphates, 39 3-9 Summary of Experimental Evidence of Developmental Effects in Mammals and Zebrafish Associated with Polyhalogenated Organophosphates, 39 3-10 Polyhalogenated Bisphenol Aliphatics, 40 3-11 Genotoxicity Data on Polyhalogenated Bisphenol Aliphatics, 41 3-12 Subchronic and Chronic Toxicity Studies of Polyhalogenated Bisphenol Aliphatics, 42 3-13 Summary of Human Epidemiologic Studies of Polyhalogenated Bisphenol Aliphatics, 43 3-14 Mammalian Developmental Toxicity Studies of Polyhalogenated Bisphenol Aliphatics, 43 3-15 Summary of Evidence on TBBPA and Changes in Thyroid Homeostasis, 44 3-16 Summary of Evidence on Developmental Effects in Mammals and Zebrafish Associated with Polyhalogenated Bisphenol Aliphatics, 44 3-17 Options and Approaches for Handling Discordant Data, 45 B-1 Sources Used to Identify Chemicals in the OFR Inventory, 60 B-2 Fourteen OFR Subclasses Formulated on the Basis of Chemotypes and Predicted Biologic Activity, 67 C-1 Number of Results of the PubChem Database Search, 79 C-2 Number of Results of the PubMed Database Search, 80 D-1 Summary of Zebrafish Studies That Evaluated Teratogenic or Developmental Neurotoxic Effects after Exposure to a Polyhalogenated Organophosphate Flame Retardant, 85 D-2 Summary of Additional Zebrafish Studies after Exposure to a Polyhalogenated Organophosphate Flame Retardant, 92 D-3 Effects of Tetrabromobisphenol A on Thyroid Homeostasis in Zebrafish, 95 D-4 Effects of Polyhalogenated Bisphenols on Zebrafish Development or Behavior, 96 D-5 Additional Zebrafish Studies of Polyhalogenated Bisphenol, 98 Prepublication Copy xi

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In the 1970s, flame retardants began to be added to synthetic materials to meet strict flammability standards. Over the years, diverse flame retardants have been manufactured and used in various products. Some flame retardants have migrated out of the products, and this has led to widespread human exposure and environmental contamination. There also is mounting evidence that many flame retardants are associated with adverse human health effects. As a result, some flame retardants have been banned, restricted, or voluntarily phased out of production and use.

This publication develops a scientifically based scoping plan to assess additive, nonpolymeric organohalogen flame retardants as a class for potential chronic health hazards under the Federal Hazardous Substances Act, including cancer, birth defects, and gene mutations.

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